Abstract
BackgroundIn hepatobiliary imaging, systems detect the total amount of agents originating from extracellular space, bile canaliculi, and hepatocytes. They add in situ concentration of each compartment corrected by its respective volume ratio to provide liver concentrations. In vivo contribution of each compartment to liver concentration is inaccessible. Our aim was to quantify the compartmental distribution of two hepatobiliary agents in an ex vivo model and determine how their liver extraction ratios and cholestasis (livers lacking canalicular transporters) might modify it.MethodsWe perfused labelled gadobenate dimeglumine (Bopta, 200 μM, 7% liver extraction ratio) and mebrofenin (Meb, 64 μM, 94% liver extraction ratio) in normal (n = 18) and cholestatic (n = 6) rat livers. We quantified liver concentrations with a gamma counter placed over livers. Concentrations in hepatocytes and bile canaliculi were calculated. Mann-Whitney and Kruskal-Wallis tests were used.ResultsHepatocyte concentrations were 2,043 ± 333 μM (Meb) versus 360 ± 69 μM (Bopta, p < 0.001). Meb extracellular concentrations did not contribute to liver concentrations (1.3 ± 0.3%). The contribution of Bopta extracellular concentration was 12.4 ± 1.9% (p < 0.001 versus Meb). Contribution of canaliculi was similar for both agents (16%). Cholestatic livers had no Bopta in canaliculi but their hepatocyte concentrations increased in comparison to normal livers.ConclusionHepatocyte concentrations are correlated to liver extraction ratios of hepatobiliary agents. When Bopta is not present in canaliculi of cholestatic livers, hepatocyte concentrations increase in comparison to normal livers. This new understanding extends the interpretation of clinical liver images.
Highlights
In hepatobiliary imaging, systems detect the total amount of agents originating from extracellular space, bile canaliculi, and hepatocytes
The maximal Meb concentrations detected by the counter in bile canaliculi (CBC) were 393 ± 61 μM and accounted for 17 ± 4% of liver concentrations
The lack of Multidrug resistance associated protein 2 (Mrp2) in cholestatic livers induced low Gadobenate dimeglumine (Bopta) canaliculi detected by the counter (CBC), increased Bopta accumulation in hepatocytes, and Bopta hepatocyte trapping during the decay period (Fig. 2c and Table 1)
Summary
Systems detect the total amount of agents originating from extracellular space, bile canaliculi, and hepatocytes They add in situ concentration of each compartment corrected by its respective volume ratio to provide liver concentrations. The function is quantified by imaging parameters such as the maximum liver enhancement or activity, the time to obtain the maximal signal, and the elimination half-life of agents from livers [5,6,7] Several hepatobiliary agents such as gadobenate dimeglumine (Bopta), gadoxetic acid, and mebrofenin (Meb) are transported inside hepatocytes across the sinusoidal Organic anion transporting polypeptide (Oatp). Besides hepatocytes, imaging relies on concentrations inside the extracellular compartment and bile canaliculi This compartmental distribution (or contribution of each compartment to liver concentrations) is inaccessible in vivo
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